IGF-I, insulin and IGF-II share common signal transduction mechanisms, reduce crypt cell apoptosis and promote transition of normal intestinal epithelium to a precancerous or cancerous phenotype. Insulin- receptor substrate 1 (IRS-1) is a common signaling intermediate for IGF (IGFIR) and insulin receptors (IR) that mediates the anti-apoptotic actions of the IGFs and insulin. Polymorphisms in IRS-1 are linked to increased colon cancer risk. EGFR, another key mediator of intestinal neoplasia interacts with IGFIR to promote survival and growth of cancer cell lines. Our recent studies defined suppressor of cytokine signaling 2 (SOCS2) as an intrinsic negative regulator of IGF-I action in the intestine. SOCS2 is silenced in cancer cell ines. SOCS2 binds directly to the IGF-IR and limits IGF-I dependent activation are linked to increased colon cancer risk. EGFR, another key mediator of intestinal neoplasia interacts with IGFIR to promote survival and growth of cancer cell lines. Our recent studies defined suppressor of cytokine signaling 2 (SOCS2) as an intrinsic negative regulator of IGF-I action in the intestine. SOCS2 is silenced in cancer cell ines. SOCS2 binds directly to the IGF-IR and limits IGF-I dependent activation of IGF-IR and IRS-1. Other data indicate that SOCS2 limits the trophic actions of EGF on the intestine. Proposed aims will test the following hypotheses. Aim #1 will test the hypothesis that IRS-1 promotes transition of normal intestinal epithelial cells to a precancerous phenotype by mediating IGF-I or insulin activation of the p-catenin signaling pathway. This aim will examine tumor growth and survival and IGF-l/insulin activation of p -catenin pathways in WT and ApcMin/+mice with 0,1 or 2 functional IRS-1 genes, and cell lines with knockdown of IRS-1. Aim #2 will test a hypothesis that IGF-IR/IRS-1 and EGF pathways interact to promote B-catenin activation and intestinal tumorigenesis. This aim will examine EGF/IGF-I interactions on B-catenin in primary I EC and model cell lines. Effects of IRS-1 deficiency combined with an EGFR inhibitor will be examined in ApcMin/+ mice. Tumors that survive inhibition of EGFR will be assessed for compensatory up- regulation of pathways that facilitate IGF-I dependent survival. Aim #3 will test the hypothesis that SOCS2 silencing promotes intestinal tumorigenesis by enhancing IGF-I activation of STAT and p-catenin pathways. This aim will examine tumor growth and survival, activation of STAT or p-catenin and local IGF-I expression in ApcMin/+ mice with 0, 1 or 2 functional SOCS2 genes. We hypothesize that SOCS2 silencing promotes tumorigenesis by dual effects on epithelium and mesenchyme. Aim #4 will test the hypothesis that SOCS2 regulates EGFR signaling. Effects of SOCS2 on EGFR activation and EGFR-induced STAT activation will be tested in cell lines and primary IEC, or tumors from SOCS2 null and WT mice with ApcMin/+ mutation or expressing a GH-transgene. An EKI-785 EGFR inhibitor will be used to directly test if EGFR mediates enhanced STAT activation in SOCS2 deficient tumors.